1 HHV-6 Foundation, Santa Barbara, California, USA.
2 Department of Pathology and Laboratory Medicine, University of Texas, Houston, Texas, USA.
3 Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
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herpesvirus 6A and 6B (HHV-6A and HHV-6B) have been noted since their
discovery for their T-lymphotropism. Although it has proven difficult
to determine the extent to which HHV-6A and HHV-6B are involved in the
pathogenesis of many diseases, evidence suggests that primary infection
and reactivation of both viruses may induce or contribute to the
progression of several lymphoproliferative disorders, ranging from
benign to malignant and including infectious mononucleosis-like
illness, drug induced hypersensitivity syndrome/drug reaction with
eosinophilia and systemic symptoms (DIHS/DRESS), and nodular sclerosis
Hodgkin’s lymphoma. Herein, we discuss the conditions associated with
the lymphoproliferative capacity of HHV-6, as well as the potential
mechanisms behind them. Continued exploration on this topic may add to
our understanding of the interactions between HHV-6 and the immune
system and may open the doors to more accurate diagnosis and treatment
of certain lymphoproliferative disorders.
Interactions between HHV-6 and the Immune System
Benign/Reactive Lymphoproliferative Disorders
|Figure 1. HHV-6B in chronic/recurrent benign lymphadenopathy. (A–D) Histological and immunohistochemical examinations on lymph node tissues. Retained normal lymph node architecture with follicular hyperplasia and concurrent mild paracortical expansion was documented on haematoxylin/eosin staining. The lymph node follicles were enlarged and numerous. There was considerable variation in the size and shape of the follicles. Most of them retained a round to oval structure, without coalescence and with a conserved mantle zone surrounding the enlarged follicles (A, magnification ×100). An intense immunopositive staining with HHV‐6B‐specific p101K antibody was demonstrated in follicular dendritic cells (FDCs) of germinal centers in the majority of hyperplastic follicles, concurrently with scattered positivity of interfollicular cells [magnification ×100 (B), ×200 (C)]. Immunohistochemical reaction for HHV‐6A (early antigen p41/38) was invariably negative on lymph node tissues (D, magnification ×400) (Forghieri et al. 2016).|
Atypical/Unusual Lymphoproliferative Disorders and Lymphocytic Infiltration
|Figure 2. HHV-6 in drug induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms.
A. Histopathology and immunohistochemistry of the lymph node. (A and B) Hematoxylin and eosin staining. Low (A) and high (B) magnification views of the cervical lymph node showed diffuse infiltration of large and blastic lymphoid cells with inclusion bodies. Intranuclear inclusion bodies were eosinophilic and had a halo (B). (C–E) Immunostaining. The large cells with intranuclear inclusion bodies were positive for HHV-6-IE (C). The HHV-6-infected cells were positive for CD25 (D) and FoxP3 (E)(Mine et al. 2014).
B. Histopathology and immunohistochemistry of the lymph node. At the cortex of lymph node, large and isolated cells were seen with hematoxylin-eosin staining (A).Many of these isolated cells were positive for HHV-6-IE and were scattered throughout the nodule (B). CD21 immunostaining showed follicular dendritic cells that presented a mesh-work like structure (C and D), in contact with several of the large lymphocytes with inclusion bodies (D). Double immunofluorescence staining showed HHV-6-IEpositive cells expressing CD3, but not CD20 (E and F). Immunostaining showed that the large lymphocytes with inclusion bodies were CD4(+) and CD8(−) (G and H)(Mine et al. 2014).
|Figure 3. HHV-6 in Hodgkin’s lymphoma.
A. a) HHV-6A in nodular sclerosis Hodgkin’s lymphoma. Hodgkin’s lymphoma, nodular sclerosing type: Left, H&E histology. Original magnification x250; b) Right HHV-6 DNA (in situ hybridization pZVH14). Original magnification x250. pZVH14 probe used was designed by and obtained from Dr. Steve Josephs at NCI/NIH. It was obtained from HHV-6A (GS Strain), and was also cross-hybridizes with HHV-6B. Probe was labelled with alkaline phosphatase, and the APAAP reaction was used (APAAP: alkaline phosphatase anti alkaline phosphatase) to visualize its tissues were subjected to in-situ-hybridization. The reaction was sensitive and highly specific as repeatedly proven by isolating HHV-6A in HSB2 cells (isolation in MOLT3 cells for HHV-6B remained negative) (With permission from G. Krueger et al.).
B. a) Presence of HHV-6 p41 by immunohistochemistry. Cytoplasmic staining of numerous large cells using a monoclonal antibody to HHV-6 p41 (3E3 clone) among NSHL specimens.
b). HHV-6 U94 detection by immunohistochemistry. Staining with monoclonal antibody to HHV-6 U94 reveals positivity in the cytoplasm of numerous large cells.
c). Presence of HHV-6 by colorimetric in-situ hybridization. HHV-6 DNA present in the nuclei of both small and large cells. (With permission from Dr. David Hudnall, Yale University, New Haven, CT, USA).
C. HHV-6 U94 PCR of Hodgkin’s lymphoma. Twenty seven of 31 (87%) HL cases were positive for HHV-6 using primers to the U94 gene. The 19 lanes in the top gel are loaded with PCR product from 19 cases of HL. The 19 lanes in the bottom gel are loaded (from left to right) with PCR product from an additional 12 cases of HL, one empty lane, two positive controls (HHV-6A, HHV-6B), one empty lane, a negative (water) control, and two empty lanes. Viral load appears to vary tremendously from case to case - in 14 cases the viral load is quite high, while in another 13 cases the viral load is very low (Siddon et al. 2012).